Astrocyte-derived adenosine modulates increased sleep pressure during inflammatory response

Glia. 2013 May;61(5):724-31. doi: 10.1002/glia.22465. Epub 2013 Feb 4.


Activation of the immune system elicits several behavioral changes collectively called sickness. Among the behavioral changes, systemic infections induce an increase in time spent in nonrapid-eye-movement (NREM) sleep and an increase of slow wave activity (or "sleep pressure"). Using an inducible, astrocyte-specific transgenic dominant negative SNARE (dnSNARE) mouse line we recently demonstrated that gliotransmission plays an important role in sleep homeostasis through an adenosine receptor 1 (A1R)-sensitive pathway. It has been hypothesized that systemic infection, mimicked by peripheral administration of lipopolysaccharide (LPS), increases sleeping behavior in part through upregulation of central adenosine levels. Moreover, as a source of immunologically relevant factors, astrocytes play a pivotal role in the central nervous system immune and inflammatory responses. However, little is known about the role of astrocytes in the CNS response to a peripheral immune challenge. We hypothesize that LPS impacts sleep homeostasis through the modulation of astrocyte-derived adenosine accumulation. We therefore used dnSNARE mice to determine whether astrocytes contribute to the increased sleep pressure under immune challenge and whether this is a result of changes in adenosine signaling. We demonstrate that dnSNARE-mediated gliotransmission is required for the ability of LPS to elevate sleep pressure as measured by the power of slow wave activity during NREM sleep. Moreover, in agreement with a role of astrocyte-derived adenosine in modulating sleep homeostasis, we find that intracerebroventricular infusion of the A1R antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) mimics this dnSNARE phenotype. Taken together, our data demonstrate that astrocytic adenosine acting through A1 receptors contributes to the modulation of sleep pressure by LPS.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine / physiology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Electroencephalography / methods
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptor, Adenosine A1 / physiology
  • SNARE Proteins / biosynthesis
  • SNARE Proteins / genetics
  • Sleep / drug effects
  • Sleep / physiology*


  • Lipopolysaccharides
  • Receptor, Adenosine A1
  • SNARE Proteins
  • Adenosine